Summary
Frontline therapy with the immune checkpoint inhibitor pembrolizumab should be considered the new standard of care for patients with microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC), according to the results of a new study. For the first time, pembrolizumab has been shown to benefit these patients when used as a frontline therapy, doubling progression-free survival (PFS) and with fewer treatment-related adverse events as compared to the current standard-of-care chemotherapy in this group of patients who typically have a poor prognosis.
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Original Article
Pembrolizumab as Firstline Therapy for Advanced Colorectal Cancer With Mismatch Repair Deficiency
Oncology Times
By Mark L. Fuerst
Frontline therapy with the immune checkpoint inhibitor pembrolizumab should be considered the new standard of care for patients with microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC), according to the results of a new study. For the first time, pembrolizumab has been shown to benefit these patients when used as a frontline therapy, doubling progression-free survival (PFS) and with fewer treatment-related adverse events as compared to the current standard-of-care chemotherapy in this group of patients who typically have a poor prognosis.
Microsatellite instability occurs in cells with high levels of mutation in short, repeated DNA sequences caused by deficiency in mismatch repair systems. About 5 percent of patients with metastatic CRC have MSI-H, which is the presence of high levels of mutations. In MSI-H/dMMR, DNA repair is impaired, resulting in an increased number of mutations. The presence of MSI-H/dMMR tumors is associated with decreased survival, and patients with MSI-H/dMMR metastatic disease are less responsive to conventional chemotherapy.
Previous research has shown good responses to pembrolizumab and longer survival for MSI-H metastatic CRC, refractory to chemotherapy. In phase II studies, pembrolizumab has demonstrated durable antitumor activity with an acceptable safety profile in previously treated MSI-H metastatic CRC. The FDA has approved pembrolizumab for previously treated MSI-H metastatic tumors regardless of tumor type or site.
“These long-awaited trial results will change clinical practice,” said lead author Thierry André, MD, Professor of Medical Oncology at the Sorbonne Université and Hôpital Saint Antoine in Paris. “Pembrolizumab works in non-randomized studies in this group of patients with advanced disease. This randomized study demonstrates a huge benefit in first line with pembrolizumab and should be the new standard of care.”
Andre presented the results of an interim analysis of the phase III KEYNOTE-177 trial at a press briefing before the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract LBA4).
About the Study
The randomized, multicenter, open-label study was designed to evaluate the efficacy and safety of pembrolizumab versus standard-of-care chemotherapy with or without bevacizumab or cetuximab as first-line therapy for patients with MSI-H/dMMR metastatic CRC in 23 countries. At the time of data cutoff for this interim analysis (February 19, 2020), the study included 307 patients. Patients were randomly assigned to receive first-line pembrolizumab for up to 2 years or the investigator’s choice of six different standard chemotherapy regimens selected prior to randomization. The investigators could choose from mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin); mFOLFOX6 plus bevacizumab; mFOLFOX6 plus cetuximab; FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan); FOLFIRI plus bevacizumab; or FOLFIRI plus cetuximab. Patients were allowed to cross over at progression from the chemotherapy group to the pembrolizumab group.
Key Findings
PFS with first-line pembrolizumab was 16.5 months compared with 8.2 months with chemotherapy with or without targeted therapy. At 12-month follow-up, the PFS rate was 53.3 percent for pembrolizumab versus 37.3 percent for chemotherapy; at 24 months the PFS rate was 48.3 percent with pembrolizumab and 18.6 percent with chemotherapy.
The objective responsive rate was also better with pembrolizumab—43.8 percent compared with 33.1 percent for chemotherapy. Some 11 percent of patients receiving pembrolizumab had complete response; one-third (33%) had a partial response and about one-third (30.9%) had stable disease. In comparison, 3.9 percent, 29.2 percent, and 42.2 percent of patients receiving chemotherapy had complete response, partial response, and stable disease, respectively. In addition, the response with pembrolizumab was more durable, with 83 percent of patients having a response longer than 2 years as compared with 35 percent of patients receiving chemotherapy.
Severe treatment-related adverse events of grade 3 or higher were also less common with pembrolizumab (22%) than chemotherapy (66%). “Clearly, there was less toxicity with pembrolizumab than chemotherapy,” said Andre. “The profile of toxicities is very different between both groups with immune-mediated adverse events with pembrolizumab (colitis and hepatitis) and classical most frequent chemotherapy toxicities for the chemotherapy arm with diarrhea, neutropenia, fatigue, nausea and vomiting, stomatis, alopecia, and neurotoxicity.”
In conclusion, Andre said: “Pembrolizumab provided clinically meaningful and statistically significant improvement in PFS versus chemotherapy as first-line therapy for MSI-H/dMMR metastatic CRC that was durable with fewer treatment-related events. We will continue to evaluate overall survival at final analysis.
“In the past, no medical treatment has shown a difference in terms of improvement of PFS in metastatic CRC,” he continued. “Today, this study demonstrates that the majority of the 5 percent of patients with metastatic CRC identified with MSI-H status benefited greatly by anti-PD-1 therapy with pembrolizumab compared to standard of care. Pembrolizumab should be the new standard of care for these patients. The hope is after stopping pembrolizumab some patients were cured of metastatic disease. These data represent another step forward for biomarker-driven studies and will help bring this approach to target MSI-H into the adjuvant and neoadjuvant setting.”
ASCO President Howard A. Burris III, MD, President and Chief Medical Officer of Sarah Cannon Research Institute, commented: “Immunotherapies like pembrolizumab have proved to be effective as second-line treatments for advanced disease. Now, in studies like this one, we are starting to see significant efficacy for immunotherapies as first-line treatment for advanced cancers with specific genetic signatures, in this case metastatic CRC with MSI-H/dMMR mutations. The data presented have the potential to change the standard of care.”
Mark L. Fuerst is a contributing writer.